Water-soluble drugs are readily injectable. Water-insoluble drugs are not. For water-insoluble (or oil-soluble) drugs the creation of injectable forms represents a substantial problem. The Pharmacopea contains many examples of water-insoluble drugs which must be taken orally because no adequate injectable form exists for them. Present art is limited in terms of the drug concentration and total volume which can be injected. Its application is limited by problems of local irritation, tissue destruction, etc. (in IM injection) and thrombophlebitis, thromboembolism, pulmonary capillary blockage, etc. (in IV injection).
As a preliminary to discussing prior art, it is useful to consider the criteria required of injectable preparations. The following criteria can be extracted from current clinical practice and from general guidelines used by the U.S. Food and Drug Administration in licensing new injectable products.
A. The preparation and its vehicle must be tissue-compatible: This requirement is equally important for injection into tissues and into the circulation. Injection of a deleterious agent into muscle can cause pain, irritation, tissue destruction, cellular reactions, fibrosis or purulent reactions. Injection of a deleterious agent into the circulation can result in thrombophlebitis, including damage to the artery or vein, clot formation in the artery or vein and blockage of the circulation to the tissue or the lungs. As described below, solubilization strategies involving the use of organic solvents, extreme pH and detergents are severely limited by these problems.
B. The formulation must not contain particles of diameter &gt;10 um: Particles with dimensions greater than 10 um will block blood capillaries. If administered intra-arterially (IA), they will lodge in the capillaries of the tissue, causing local ischemia. If administered IV, they will lodge in the lung capillaries and cause respiratory distress. For reasons of safety, the &lt;10 um criterion must be met for other intended routes of injection (e.g., intra-muscular, IM) due to the danger of inadvertent IV or IA injection. As described below, most of the controlled release technology directed at oral dosing is inapplicable to injectable forms because it fails to meet this criterion.
C. The formulation must allow injection of sufficient quantities of drug: The formulation must carry the drug at high concentration. As an example, if the highest concentration available for a drug is 2% (w/v) or 20 mg/ml and the largest practical volume for an IM injection into man is 5 ml, then a single injection can supply only 100 mg of the drug. If the drug is sufficiently potent, this will present no problem. However, there are many examples in which 1-2 gm of drug must be introduced into the body. This would require either a 10- or 20-fold larger volume (impractical or impossible) or 10-20 times the concentration (heretofore unachievable).
D. The formulation must not rely on constituents which may elicit an allergic response: This is a particular problem for injections into the skin and muscle. Repeated injections of foreign proteins or macromolecules can elicit an immune response. Much of the present art in controlled release relies on "plastics", crosslinked serum albumin, or polymers such as poly (D,L) lactic acid.
E. To be generally useful, the delivery system must have a high "payload": Payload can be defined as the ratio of weight drug delivered to weight of carrier, or encapsulating substance. For example, if a delivery system uses 10 gm of wax or polymer to encapsulate 2 gm of drug, then its payload is 0.2. Delivery systems with low payload will require large amounts of encapsulating substance. The ability of the tissue or vascular compartment to metabolize or remove this substance, however benign, will limit the amount of drug which can be given.
F. The formulation must be stable, grossly homogeneous, syringable and pharmaceutically elegant and must maintain these properties for a reasonable shelf life: The phospholipid-coated microcrystal disclosed in this specification is unique in that it satisfies all of these criteria. It is also unique in that, while satisfying the above criteria, it enables water-insoluble drugs to be injected at high concentrations as high as 40% (w/v).